Lecture%2019%20Homework%20Review%20Apoptosis%20and%20Cancer

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Lecture 19Homework ReviewApoptosis and Cancer
Office Hours This Week Today 530- 730pm

• Next Two Lectures
• Cell-Cell Interactions/Tissues
• Early Development and Stem Cells
• For Exam III- You are not responsible for any
  material in assigned chapters relating to Plants!

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ApoptosisRegulated Cell Death
Role in Killing of Unneeded, Damaged, or
Potentially Deleterious Cells Occurs in
Embryonic and Adult Tissues Proteins Involved are
Always Present in Cells- Needs to Be Activated by
Stimuli Can Result From Developmental
Cues Withdrawl of Essential Growth Factors DNA
Damage Various Cell Stresses
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Programmed Cell Death

• Cell Death Occurring at a Defined Point in
  Development
• Usually proceeds by Apoptosis

Mouse Paws
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Not All Cell Death is Apoptotic
Apoptosis An Active Regulated Process DNA
Fragmentation Chromatin Condensation
Fragmentation of Nucleus Cell Shrinks
Formation of Membrane Enclosed Fragments called
Apoptotic Bodies Recognition and
Engulfment by Phagocytic Cells
or Neighboring Cells

• Oncosis and Necrosis
• Unregulated Cell Death Due to Injury
• Cell Swells (Oncosis)
• Nucleus Swells
• Disruption of Organelles and Rupture/Release of
  Contents
• Contents Released into
• Extracellular Space

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The Morphological Changes of Apoptosis Are
Orchestrated by Caspases
Cysteine Proteases that cleave at Aspartic Acid
Residues Activate Apoptosis by Cleaving
Specific Substrates Present but inactive in
cells Two Main Types of Caspases 1)
Initiators- Need to dimerize to become active
induced proximity 2) Executioner (Effector)
- Need to be proteolytically cleaved to become
active - Cleavage is usually Mediated by
Initiator Caspases
Zymogens
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Caspase Activation Amplification Cascade

• Once Executioners are Activated their
• Key Targets of Proteolysis Include
• 1)An Inhibitor of a DNAse-
• Leads to Fragmentation of DNA
• 2)Nuclear Lamins-
• Leads to Fragmentation of Nucleus
• 3)Other Cytoskeletal Associated Proteins-
• Leads to Disruption of Cytoskeleton and
• Cell Fragmentation
• 4)Additional Caspases

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Main Pathways Regulating Caspase Activation
During Apoptosis

• Intrinsic Pathway- Mitochondrial Mediated
• Major Pathway in Mammalian Cells
• Outer Mitochondrial Membrane Permeabilization
  (MOMP)
• Release of Cytochrome C from Mitochondrial
  Intermembrane Space into Cytosol
• Apoptosome Formation- Activation of Initiator
  Caspase
• Effector Caspases Activated
• Extrinsic Pathway- Signaling through Death
  Receptors
• Ligand Bound Death Receptors
• Adaptor Protein Association
• Initiator Caspase Recruitment and Activation
• Effector Caspases Activated

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Intrinsic Pathway of Apoptosis Activation
MOMPs cytochrome c Release Apoptosome
Formation Adaptor (Apaf1), dATP cytochrome c
and procaspase complex
Association of Adaptor with Procaspase allows
Procaspase self cleavage
Active Initiator Caspase Cleaves Effector
Caspases Which now Cleave Targets
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Critical Regulators of Cell Death

• Bcl-2 Family Regulate whether MOMPs Occurs
• Anti-Apoptotic Factors - Death Inhibitors
• A) Function to Inhibit MOMPs by Pro Apoptotic
  Factors
• Pro-Apoptotic Factors- Death Activators
• A) Bind and inhibit Death Inhibitors
• B) Directly cause Permeabilization of MOM to
• Stimulate Release of Cytochrome C ( BAX
  AND BAK)
• IAP Family (Inhibitor of Apoptosis)
• Bind Procaspases prevent activation
• Bind Caspases and inhibit Activity

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Survival Factor Signaling is Required to Prevent
Apoptosis
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Programmed Cell Death in Neuronal Development
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Survival Factors Signaling Can Function to Keep
Anti-Apoptotic Factor Bcl-2 Active
No Survival Signal Bcl-2 Complexes with
Bad Cant prevent BAK and BAX Mediated MOMPs
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Extrinsic Pathway of Apoptosis ActivationSignali
ng through the Death Receptors
Ligand Bound Death Receptors Adaptor Protein and
Procaspase Recruitment Initiator Caspase
Activation Effector Caspases Activated
Target cells Viral Infected Cells or Cancer
Cells Removal of Excess Lymphocytes
after Infection
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Cancer

• Cancer is a Disease of Cells that Proliferate at
  Inappropriate Times and Locations in the Body.
• Tumors (Neoplasms) - Masses of cells derived from
  a single abnormally proliferating cell. Tumors
  are Clonal
• 1. Benign- Noninvasive, Do not affect other
  tissues
• 2. Malignant- Cancerous, Locally Invasive and May
  Spread
• Tumors are classified by cell type from which
  they arise.
• 1. Carcinoma- 90 of human cancers- Malignacy of
  Epithelial Cells
• 2. Sarcomas Rare, Solid tumors of connective
  tissue, such as bone, muscle, cartilage, and
  fibrous tissue.
• 3. Leukemias and Lymphomas- 7 of cancers, Blood
  forming cells and cells of immune system
• 4. Neuroectodermal- Cells of central or
  peripheral nervous system

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The Development of Cancer is a Multistep Process
Initial Cell Proliferating Abnormally
Tumorigenesis Occurs by Clonal Expansion
Yields Population of Cells More Abnormal and
More Adapted Proliferate, Survive, Invade and
Metastasize Intravasation Malignant cells gain
access to blood vessels and lymphatic system
and spread Metastasis Malignant cells
Establish in distant organs

Typically requires four to six different
mutations
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Cancer Cells are Characterized by Several
Distinct Properties when Grown in vitro

• Key Characteristic Normal Cell Cancer
  Cell
• Contact Inhibition of Growth Present Absent
• Growth Factor Requirements High Low
• Anchorage Dependence Present Absent
• Cell Cycle Checkpoints Intact
  Absent
• Karyotypic Profile Normal
  Abnormal
• Proliferative Life Span Finite
  Indefinite
• Cancer cells are also
• Defective in Differentiation
• Fail to Undergo Apoptosis

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Cancer Cells Are Created when Certain Genes are
Mutated

• Mutations can be Inherited, Introduced by
  Viruses, or Result of DNA Damage (exposure to a
  mutagen)
• 1. Oncogenes - Gene whose presence can trigger
  inappropriate cell proliferation.
• Example ras, bcl-2
• (Normal version of gene Proto-oncogene)
• 2. Tumor Suppressors- Gene whose absence or
  inactivation can lead to cancer
• Usually Function to Block Cell Cycle
  Progression
• Example p53, Rb
• DNA Repair Genes- Increase Rate of Mutation,
  provide opportunity for mutation in growth
  controlling genes, increase rate of tumor
  progression

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Cancer Cells Are Created When Certain Genes are
Mutated
Activation of Oncogene
Can Also Occur By Overexpression of
Proto-oncogene Translocations that create
hybrid proteins
Inhibition of Tumor Suppressor Genes
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Oncogenes are Found in Mitogen andGrowth Factor
Signal Transduction Pathways
Mutation of Proto-oncogene- Constitutively
Active Downstream Signal Transduction Pathway
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Inactivation of Tumor Suppressor Rb
Common Target for Viruses that Cause Tumors
(along with p53)
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Cancer Cells Exhibit Unlimited Proliferative
Ability

• Cancer cells avoid senescence by inactivating
  tumor suppressor genes, p53 and Rb.
• Cancer Cells will continue to divide for a period
  of time
• Crisis Point Large number of Cancer Cells Die-
  Result of catastrophic rearrangements- due to
  lack of telomerase
• Rare Occasion A Cell Survives- It is
  Immortalized.
• At some point- derepressed telomerase expression
• 90 of cancer cells express
• significant levels of telomerase